The pain is defined as an unpleasant sense which is accompanied by existing tissue damage or is expressed from such an experience, or an experience of an emotional action (International Association for the Study of Pain, 1979), and is divided into an acute pain and a chronic pain.
In the acute pain, a nociceptive stimulus which violates a tissue of the biological body is input into a peripheral nociceptor, converted into an action potential and transferred as an impulse to the spinal cord, at which it is influenced by various inhibitory system such as descending system, and ascends the sensory transfer system and reaching the cerebral cortex, so that the acute pain is recognized. That is, the acute pain is a physiological pain caused by a nociceptive stimulus, and has a significance as a warning reaction in the biological body. The acute pain disappears by cancellation of the nociceptive stimulus or healing of the injury.
On the other hand, the chronic pain is a pain which is complained regardless of the healing of tissue injury or a pain which is complained regardless of the absence of evident tissue injury. That is, the chronic pain is “a pain which is complained regardless of exceeding the period generally necessary for healing of the disease, or a pain related to progressive non-cancerous diseases”.
The chronic pain does not have a physiological significance as a biological body warning system unlike the case of acute pains and, what is more, it greatly spoils quality of life of patients. Thus, the chronic pain is an independent disease and requires a treatment, namely elimination of pain, but most cases of the chronic pain are intractable.
The fibromyalgia is a disease which has a systemic unbearable chronic pain as the core symptom accompanied by various comorbid symptoms such as sleeplessness, systemic fatigue feeling, depressive symptom and the like. Diagnostic standards of the American College of Rheumatology are the continuation of a pain over broad range of the body for 3 months or more and the presence of tenderness at 11 points or more among the 18 tender points on the whole body (ligaments, tendons, muscles and the like contacting with bones). It is sometimes accompanied by a pain caused by a tactile stimulus or cold stimulus which does not generally cause a pain, called tactile allodynia or cold allodynia. In addition, it is also frequently accompanied by a thermal hyperalgesia in which sensitivity for thermal stimulus is accelerated. Since prevalence rate of fibromyalgia is about 2% of the population, a considerably large number of patients are present. However, since a sufficiently effective therapeutic method is not present, concern has been strongly directed toward the development of a new therapeutic method having high efficacy.
Pathophysiological mechanism of fibromyalgia is not sufficiently revealed. Since the systemic unbearable chronic pain and various comorbid symptoms such as sleeplessness, systemic fatigue feeling, depressive symptom and the like, as the characteristics of fibromyalgia, cannot be fully described by a peripheral level abnormality, it is considered that an abnormality of pain-controlling mechanism of the central nervous system is participated in the pathophysiological mechanism of fibromyalgia (e.g., see Non-patent Reference 1). Actually, results of studies which used a functional magnetic resonance imaging (fMRI) and a single-photon emission tomography (SPET) show that there is an abnormality in the brain function of fibromyalgia patients (e.g., see Non-patent References 2 and 3).
Quantitative changes and functional abnormalities of various neurotransmitters, cytokines or hormones are suggested on fibromyalgia patients. Concentration of excitatory amino acid, substance P or nerve growth factor in the cerebrospinal fluid of fibromyalgia patients is higher in comparison with that of the non-patient groups. On the other hand, metabolite concentration of serotonin, dopamine or norepinephrine in the cerebrospinal fluid of fibromyalgia patients is lower in comparison with that of the non-patient groups (e.g., see Non-patent Reference 4). It has been reported that there is a correlation between the amount of excitatory amino acid as a brain excitatory transmitter in brain insula and the pain level of fibromyalgia patients (e.g., see Non-patent Reference 5).
In addition, it has been reported that there is an abnormality in the release mechanism of brain dopamine for a pain stimulus in fibromyalgia patients (e.g., see Non-patent Reference 4). Cytokines such as interleukin-1 and tumor necrosis factor (Tumor Necrosis Factor) have been detected from the skin tissue of fibromyalgia patients (e.g., see Non-patent Reference 6). In addition, it has been suggested that the secretion function of growth hormone or insulin-like growth factor (IGF) is reduced in fibromyalgia patients (e.g., see Non-patent Reference 4). Thus, a possibility has been suggested that many neurotransmitters, cytokines or hormones and the like are contributed to the pathophysiological mechanism of fibromyalgia, but it has not been revealed yet that which change is the causal pathogenesis and which one is the consequent phenomenon. That is, pathophysiological mechanism of fibromyalgia has not been revealed yet (e.g., see Non-patent Reference 6).
Recently, it has been reported that pregabalin (a nerve Ca2+ channel ligand), duloxetine (a selective serotonin and norepinephrine reuptake inhibitor) or pramipexole (a dopamine receptor agonist) alleviates the pain symptom score of fibromyalgia patients statistically significantly in comparison with the placebo group (e.g., see Non-patent References 7 to 9).
However, effects of these drugs are limited, and there is no therapeutic method yet which is sufficiently effective on the pain-centered symptoms of fibromyalgia patients. Accordingly, there is a strong demand for the development of a further excellent therapeutic agent which has sufficient effects and shows fewer side effects.
In general, validity of a disease animal model is evaluated from the viewpoint of face validity (whether or not the model and human disease symptomatically resemble), construct validity (whether or not the model is based on the theoretical ground) and predictive validity (whether or not the effects of therapeutic agent in the model and clinical setting are correlated). As the disease animal model of the chronic pain which is accompanied by muscle pain, there have been reported a method in which carrageenan or acidic water is intramuscularly injected (e.g., see Non-patent References 10 and 11) and a method in which a repeated forced swimming load is applied (e.g., see Non-patent Reference 12). However, there has not been reported so far on an animal model which sufficiently reflects the pathophysiological mechanism of fibromyalgia from the viewpoint of face validity, construct validity and predictive validity.
Regarding the pain inducing action of reserpine, it has so far been reported that single intraperitoneal administration of reserpine causes hypersensitivity to thermal stimulation in rats. However, it has been reported that this hypersensitivity to thermal stimulation is a transient acute pain which disappears within 24 hours (e.g., see Non-patent Reference 13). Induction of the generation of a pain by reserpine over a long period of time of 1 day or more has not been reported yet.    Non-patent Reference 1: Nature Clinical Practice Rheumatology, 2006, vol. 2, p. 90-97    Non-patent Reference 2: Journal of Rheumatology, vol. 31, p. 364-378    Non-patent Reference 3: American journal of the Medical Science, 1998, vol. 315, p. 385-396    Non-patent Reference 4: Current Opinion in Investigational Drugs, 2007, vol. 16, p. 829-841    Non-patent Reference 5: Arthritis & Rheumatism, 2008, vol. 58, p. 903-907    Non-patent Reference 6: Joint Bone Spine, 2008, vol. 75, p. 273-279    Non-patent Reference 7: The Journal of Rheumatology, 2008, vol. 35, p. 502-514    Non-patent Reference 8: Pain, 2008, vol. 136, p. 432-444    Non-patent Reference 9: Arthritis & Rheumatism, 2005, vol. 52, p. 2495-2505    Non-patent Reference 10: Pain, 2000, vol. 35, p. 333-343    Non-patent Reference 11: Muscle & Nerve, 2000, vol. 24, p. 37-46    Non-patent Reference 12: Physiology & Behavior, 2006, vol. 88, p. 82-87    Non-patent Reference 13: European Journal of Pharmacology, 1982, vol. 83, p. 325-328